Results of Phase l studies with new recombinant strains of attenuated Salmonella typhi (e.g. CVD9O8) used as live oral vaccines suggest that these well-tolerated oral vaccines can elicit potent immune responses and can effectively deliver foreign proteins such as the circumsporozoite protein of Plasmodium falciparum (CSP) to the human immune system. Preliminary data from clinical vaccine trials using CVD9O8 alone or carrying the gene encoding CSP indicate that CVD9O8 can effectively induce strong systemic immune responses to the vector while expressing CSP. Anti- S. typhi responses induced by CVD9O8 predominantly involve the production of type 1 cytokines. The overall goal of this research is to establish the basis for systemic immunity to the vector and to explore the notion that antigen competition may be due in part to the generation of antagonistic sets of cytokines by the individual components of a combination vaccine. To better understand the role of systemic immunity in the response to the vector and to the foreign protein, we will investigate the molecular basis for cytotoxic T lymphocyte and T helper responses in cloned cells derived from peripheral blood mononuclear cells from volunteers immunized with CVD9O8 or CVD9O8-CSP constructs. Further, we will test the hypothesis that induction of type 2 cytokines by the foreign protein may inhibit the responses against the vector and may represent one possible mechanism for antigen competition. The information obtained will be valuable for the design of more immunogenic combination live vector vaccines.